DESCRIPTION: Low back pain will affect up to 85 percent of people at some point during their lives, resulting in healthcare and related costs to the United States economy in excess of $100 billion every year. Among Veterans, chronic low back pain accounts for over 70 percent of chiropractic visits and in many cases is directly connected to their period of service. Intervertebral disc degeneration, a progressive, inflammation driven cascade that leads to structural and mechanical failure, is strongly implicated as a cause of low back pain. Between 2001 and 2010, more than 130,000 active service members received diagnoses of disc degeneration, with annual incidence rates more than doubling over this period. Developing new treatment strategies for disc degeneration is therefore highly relevant to both active military personnel and Veterans. A key limitation of current treatments for disc degeneration is that they do not seek to maintain or restore native tissue structure and mechanical function. There is therefore a strong need for new therapies for disc degeneration that retain and/or restore disc structure and mechanical function by directly addressing the underlying causes and mechanisms. The ideal therapy for disc degeneration would: 1) be minimally invasive; 2) restore biomechanical function; 3) attenuate localized inflammation driving tissue catabolism; and 4) potentiate long term extracellular matrix regeneration. We have recently developed a novel injectable hydrogel that polymerizes rapidly in the absence of exogenous cross-linking agents, supports mesenchymal stem cell survival and biosynthesis, and normalizes disc mechanical function. We have also developed a novel sustained release therapy for disc inflammation using interleukin-1 receptor antagonist (IL-1R?) delivered from polymeric microspheres. The objective of this proposal is to synergize these technologies to develop a minimally invasive therapy that simultaneously normalizes disc mechanical function, attenuates localized inflammation, and promotes stem- cell driven native tissue regeneration. We hypothesize that only by addressing these criteria will a therapy for disc degeneration have long-term efficacy. In Aim 1 we will establish in vitro techniques for preconditioning stem cells to survive in the harsh in vivo microenvironment of the disc, verify the efficacy of preconditioning in vivo, and establish the optimum in vivo seeding density which balances maximum regeneration potential with the limited nutritional availability inherent to the implantation environment. In Aim 2 we will extend our previous work to develop and test an anti-inflammatory therapy that attenuates the complex inflammatory cytokine expression profile present in the degenerate disc, with the dual objectives of preserving stem cell regenerative potential and halting continued native tissue destruction. Finally, in Aim 3, as a critical pre-clinical step we will evaluate this therapeutic strategy in an established large animal model of disc degeneration.